Background: Ponatinib, a third-generation BCR::ABL TKI, has potent activity against all clinically relevant BCR::ABL1 variants, including T315I. PhALLCON (NCT03589326), a phase 3 trial comparing frontline TKIs in adults with Ph+ ALL, met its primary endpoint with a higher rate of minimum residual disease–negative (MRD-neg) complete remission (CR) at end of induction (EOI) with ponatinib vs imatinib (34.4%/16.7%; P=0.002). Here, we report response rates of MRD-neg at any time and PFS by age and BCR::ABL1 variant subgroups. Methods: Adults with newly diagnosed Ph+ ALL were randomized 2:1 to ponatinib (30 mg QD reduced to 15 mg QD upon MRD-neg CR at or after EOI) or imatinib (600 mg QD) plus 20 cycles of reduced-intensity chemotherapy (induction: 3 cycles; consolidation: 6 cycles; maintenance: 11 cycles), followed by single-agent ponatinib or imatinib until disease progression or unacceptable toxicity. Hematopoietic stem cell transplant (HSCT) was per investigator’s discretion. Post hoc analyses compared MRD-neg (BCR::ABL1^IS≤0.01%; MR4) at any time and PFS (any-cause death, failure to achieve CR by EOI, relapse from CR, or failure to achieve/loss of MRD-neg) by age (</≥65 y) and BCR::ABL1 variant (p190/p210). Data cutoff: Aug 12, 2022. Results: In the population of randomized patients (pts) with p190/p210 confirmed by central lab (n=232; 154/78 ponatinib/imatinib; median follow-up 20.1 mo), 68% vs 50% in the ponatinib vs imatinib arms were MRD-neg at any time, with similar benefit of ponatinib across age and variant subgroups (Table). Median PFS was more than twice as long with ponatinib vs imatinib across subgroups (Table). Pts achieving MRD-neg at any time were less likely to have HSCT with ponatinib vs imatinib (32%/56%). Among 107/42 pts without HSCT, exposure was >2-fold longer in the ponatinib vs imatinib arms (median 12.8/5.1 mo) with comparable rates of arterial occlusive (3%/2%) and venous thromboembolic events (11%/12%), and discontinuations due to TEAEs (13%/14%). Conclusions: Ponatinib was superior to imatinib in combination with reduced-intensity chemotherapy for frontline treatment of Ph+ ALL, with higher rates of MRD-neg at any time, substantially longer PFS across age and BCR::ABL1 variant subgroups, and a safety profile comparable to imatinib. Clinical trial information: NCT03589326.

*95% CI did not include 1.00.